Multiple Sclerosis · Clinically Isolated Syndromes • Transverse Myelitis – Risk factors for MS...

Multiple SclerosisM.Sykora

• Chronic autoimmune disease• Progressive disease• Involves Immune System & Neurological

System • Multifocal areas of demyelination• Disrupts ability of the nerve to conduct

electrical impulses• Leads to symptoms

MultipleSclerosis

Epidemiology of MS

• Age onset 20 – 50 years old• Women are 2 times more likely to develop MS• Over 2.5 million people around the world• More prevalent whites of northern European

ancestry• Genetic Influences

MSPathophysiology• Autoimmune inflammation, starts in the periphery• affects only CNS• affects primarily “white matter”• Foci of inflammation = demyelinization = destruction

The causes:interplay between environment and genetic factors

Environmental factors

Genes

Post genomic modifications

MS

Pathogens – molecular mimicry

ChemicalsDiet

Geography

Gene rearrangementsSomatic mutations

RetroviralmRNA splicing

Genome allelic variations Monozygotic twins 30%

Linkage and association studies

MultipleSclerosis

MSPathology

MSPathology

HC RRMS SPMS

Degeneration of chronically demyelinated axons:Loss of trophic support. SPMS.

Brain atrophy in MS

Source: National Multiple Sclerosis Society & NIH estimates

Clinical Forms of MSRelapsing-remitting

(RRMS): 55%

Secondary Progressive (SPMS): 35%

Primary Progressive (PPMS) 9%

Progressive Relapsing

(PRMS): 1%

• Clearly defined flare-ups & remissions; inflammatory lesions developing constantly

• Early 20s & 30s; women 2:1• Initial disease activity in brain

(cognitive)• Better prognosis: supporting

equipmentavg. 20 yrs

• Majority of RRMS pts will develop SPMS(90% in 25-30 years)

• Relapse frequency decreases but disability increases• Less remyelination & more plaques, resulting in steadily progressive disability with less recovery• Could represent different, advanced stage of RRMS

• At onset, steady worsening without relapses or remissions

• Variations in rates of progression; occasional plateaus or temporary minor improvements

• Late 30s/early 40s; men as likely as women

• Initial disease activity in spinal cord (physical disability)

• Worse prognosis: supporting equipment avg. 6-7 yrs

• From onset steadily worsening disease with clear acute relapses with or without recovery

• Unlike RRMS, remission periods contain clinically observable continuing disease progression

Clinical forms change with the time

Relapsing MS and Progressive MSThese two classifications are critical to understanding the current & future treatment paradigms

Sources: National Multiple Sclerosis Society; http://www.multsclerosis.org/progressiverelapsingmultiplescler osis.html

RRMS PPMSSPMS

Treatment Objective:Address the degenerative component• Slow disability progression

Treatment Objective:Address the inflammatory component• Prevent new attacks• Improve MRI outcome• Slow disability progression

Relapsing MSRRMS, worsening RRMS,

SPMS with relapses

Progressive MSSPMS without relapses, PPMS

Preclinical forms: CIS and RIS

• Clinically isolated syndrome (CIS) =„ an initial neurologic event suggestive of demyelination „

• Radiologically Isolated Syndrome (RIS)= “asymtpomatic individuals who possess radiologic

abnormalities highly suggestive of multiple sclerosis”

Symptoms of MS

• Vision problems• Numbness• Difficulty walking• Fatigue• Depression• Emotional changes• Vertigo & dizziness• Sexual dysfunction

• Coordination problems

• Balance problems• Pain• Changes in cognitive

function• Bowel/bladder

dysfunction• Spasticity

Initial Presentation of MSIncidence (%)

Optic nerve inflammation 14–29

Poor balance (ataxia) 2–18Dizziness (vertigo) 2–9Weakness (paresis) 10–40Double visions (diplopia) 8–18Bladder, bowel dysfunction 0–14

Pain 21–40Sensory loss 13–39

EDSS Scale

Diagnosis

• McDonald Criteria 2010• At least two episodes of symptoms

– Occur at different points in time (DIT)– Result from involvement of different areas of the central

nervous system (DIS)• Absence of other treatable causes for the symptoms• Results of neurological testing

DiagnosisDIS clinical:

• objective clinical evidence of involvement of at least two CNS sites

• or objective clinical evidence of one lesion with reasonable historical evidence of another site being affected.

DiagnosisDIS MRI: • minimum two lesions: at least one T2 lesion in at least

two of the four sites typically affected by multiple sclerosis (periventricular, juxtacortical, infratentorial, or spinal cord).

Diagnosis

Typical MRI

DiagnosisDIT clinical: ● criteria may be satisfied on clinical grounds alone if the

patient has a history of at least two attacks● If the patient has a history of one attack, MRI criteria

may be applied to establish DIT.

DiagnosisDIT MRI: ● DIT can be established with the development of a new

T2 lesion at any time, compared to a baseline scan performed at any time

● In certain cases, DIT can actually be established with a single MRI scan (old and new lesions)

Diagnostic work up• History & Physical Exam• Brain and Spinal Cord MRI• Labs: rule out mimics of MS

– Connective tissue diseases, infections, metabolic disorders

• Cerebrospinal Fluid (when clinical and MRI evidence inconclusive)

• Evoked Potentials: – Identify damage to visual, auditory, & touch perception

systems– Less sensitive than MRI or cerebrospinal fluid

Diagnostic work up

CSF Analysis

• Elevated IgG Index >0.7 – Increased CNS IgG synthesis,

with normal serum IgG consistent with MS

• Oligoclonal Bands – Presence of ³2 distinct bands

in CSF is consistent with MS

• Most helpful for suggesting an alternative Dx-high protein, marked pleocytosis, lympho-/monocytes

OCBs not only in MS• Lupus 25%• Sarcoidosis 51%• Behcet’s 8%

• Syphillis• CJD• Whipple’s disease• Lyme disease• Vaculitidies• Devic’s disease• Healthy siblings of MS

patients

MS Variants• Marburg variant (monophasic, mass effect)• Balo’s Concentric Sclerosis (lamellar lesions)• Schilder’s Disease (children, large, bihemisferic

lesions)

MS Variants

• Neuromyelitis Optica (Devic)– Relapsing (55%), monophasic (35%)– Optic neuritis + 3 segments spinal– MRI: cord lesions, chiasmal signal changes– CSF: generally >100 wbc, ­protein, rare OCB– NMO IgGs (anti-aguaporin4 IgG antibodies)

• Postinfectious encephalomyelitis or ADEM– Monophasic with preceeding event common (70%)– Most common in children– Altered LOC and seizures common– MRI: bilateral symmetric lesions

Clinically Isolated Syndromes• Optic Neuritis

– Risk factors for MS (60-75%)• History of minor neurologic sxs• Unilateral optic neuritis• Brain MRI lesions• Abnormal CSF• Abormal VERs

Clinically Isolated Syndromes • Transverse Myelitis

– Risk factors for MS• Incomplete transverse myelitis• Asymmetric motor or sensory findings• Brain MRI lesions• Abnormal CSF• Abnormal VER and SSEPs

• Others (Brainstem, Cerebellum)

Lhermitte sign

• electric shock-like sensations that run down the back and/or limbs upon flexion of the neck

Uhthoff phenomenon

• small increases in the body temperature can temporarily worsen current or preexisting signs and symptoms

• This phenomenon is presumably the result of conduction block developing in central pathways as the body temperature increases

Diseases to rule out

• Viral infections• Lyme disease• B12 deficiency• Lupus• Rheumatoid

arthritis• Other connective

tissue disorders

• Vasculitis• Syphilis• Tuberculosis• HIV• Sarcoidosis

Management

• Immunosupression/Immunomodulation– Treatment of exacerbations– Prevent the occurrence of future attacks

• Symptomatic therapy• Physical therapy• Psychosocial support

Treatment of New MS Exacerbations

– Corticosteroids 5 days x 1g IV– Intravenous immunoglobulin (IVIG)– Plasma exchange (PE)

• Physical therapy

MS Therapy

PreventionofFutureAttacksandDiseaseProgression

MS Therapy

MS Therapy: PML• key safety concern • serious, often fatal opportunistic infection of

oligodendrocytes caused by reactivation of latent (JC) polyomavirus

• occurs with nalazumab, dimethylfumarate

• MRIs intermittently during therapy• JCV antibody leves and JCV PCR • Thx: PE/IA, mirtazapine, mefloquine

MS Therapy: PML-IRISImmune ReconstitutionInflammatory Syndrome (IRIS)

• paradoxical deterioration in clinical status attributable to recovery of the immune system

• MRT lesion growth, contrast enhancement, edema

• Thx: corticosteroids, mannitol

Side effects of MS medication• Local injection site irritation/reactions• Flu like symptoms• Rise in liver enzymes• Decreased white cell count and platelets• Opportunistic infections• Depression• Progressive multifocal leukoencephalopathy (PML)

Fatigue• Medications

– Amantadine– Methylfenidate– Modafinil

Cognitive Changes

• Teach to make lists• Use calendar for

appointment & special dates

• Use tape recorder to help remember information

• Start a diary or memory notebook

• Organize environment

• Limit noise during conversations

• Have patient repeat information and write down important points

• Encourage use of crossword puzzles and cognitive function tests

• Medications– Aricept– Memantin– Exelon

Bladder problems• Rule out UTI• Bladder training

– Strengthen pelvic muscles

• Medication• Anti-spasticity

– Solifenacinsuccinat – Tolterodine – Oxybutinine

• Referral to urologist for further evaluation and treatment

Sexual Dysfunction• Medications

– Sildenafil– Tadalafil– Vardenafil

Constipation

• Increase oral intake• Increase fiber intake• Laxatives

Spasticity and mobility• Baclofen• Diazepam, Tetrazepam• Tizanidine• Intrathecal baclofen• Cannabinoids• Botulotoxin

• Fampridin

Depression• SSRI• TCA• SRNI

Thank you!